Antivirals_FAR382 2024.pdf

Department of Pharmacology FAR 382 Antivirals Department of Pharmacology [email protected] 1  Characteristics of a Virus 1. Non-cellular organism ▪ Dependent on host system...

Department of Pharmacology FAR 382 Antivirals Department of Pharmacology [email protected] 1  Characteristics of a Virus 1. Non-cellular organism ▪ Dependent on host systems for reproduction & metabolism 2. Very small in size ▪ 20 – 1400 nm 3. Free-living virus particle is known as a virion Structure: ▪ Viral nucleic acid (RNA or DNA) enclosed in a protein coat known as a capsid ▪ Some viruses have an envelope outside the capsid ▪ Envelope has spikes which help with attachment to host cell ▪ Viruses without envelope around capsid are known as naked viruses (these are more virulent) Image adapted from: https://www.differencebtw.com/difference-between-enveloped-and-non-enveloped-virus/  Viral Replication 1. DNA viruses ▪ Enter host cell nucleus and direct generation of new viruses Image adapted from: Gerard J. Tortora, Berdell R. Funke, Christine L. Case, Microbiology: An Introduction, 12th Edition. Pearson Education Inc, © 2016  Viral Replication 2. RNA viruses ▪ Generate new viruses without host cell nucleus, with the exception of the influenza virus Image adapted from: https://thegeneticsofvirusesandbacteria.weebly.com/diagrams.html  Viral Replication 3. RNA retroviruses ▪ Make cDNA copies of viral RNA via reverse transcriptase ▪ cDNA copies are integrated into host cell genome and direct generation of virus particles Image adapted from: https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/19/73/the-hiv-life-cycle  Viral Pathologies DNA viruses RNA viruses Small pox (pox virus) Influenza (orthomyxovirus) Shingles, glandular fever, cold sores (herpes Measles, mumps, respiratory tract infections viruses) (paramyxoviruses) Sore throat (adenovirus) Rabies (rhabdovirus) Warts (papillomavirus) Colds, meningitis, polio (picornaviruses) HIV/AIDS, T-cell leukaemia (retroviruses) ▪ Herpes viruses (e.g HSV-1 & 2), Influenza viruses, HIV are responsive to antiviral therapy ▪ Mumps, polio, rabies, rubella are not responsive to antiviral therapy. Vaccines are available for these viral diseases to prevent infections  Antiviral Therapy ▪ Antivirals are virustatic rather than virucidal ▪ Therefore, they rely on host immuno-competence ▪ Antivirals seldom affect latent viruses ▪ Main reasons why viruses are problematic to treat: 1. Antivirals do not exhibit selective toxicity (viral integration into host DNA) 2. Viral latency - most antivirals are effective only when virus is replicating 3. Initial phases of viral infection are often asymptomatic & treatment is often delayed until the infection is well established. 4. Rapid mutations which allow viruses to evade detection and be resistant to treatment  Classes of Antiviral Drugs Nucleoside / nucleotide reverse DNA polymerase inhibitors transcriptase inhibitors Neuraminidase inhibitors Non-nucleoside reverse transcriptase inhibitors Biologics and Protease inhibitors immunomodulators Fusion/entry inhibitors Integrase inhibitors *e.g., for herpes, influenza, hepatitis * e.g., for HIV  Sites of Action of Antiviral Drugs Image adapted from: Mohamed G. Atta, Sophie De Seigneux and Gregory M. Lucas. 2018. Clinical Pharmacology in HIV Therapy. CJASN, CJN.02240218; DOI: https://doi.org/10.2215/CJN.02240218  DNA Polymerase Inhibitors: MOA MOA explained using acyclovir as an example: ▪ Acyclovir (guanosine analogue), is phosphorylated to acyclo-guanosine monophosphate (GMP) in the cell by the viral thymidine kinase enzyme ▪ GMP is converted to the Acyclovir di- and triphosphate (GTP) forms by the host cell kinases. resistance ▪ Acyclovir- GTP competes with deoxyguanosine triphosphate (a nucleotide) as a substrate for viral DNA polymerase and is itself incorporated into the viral DNA, causing premature DNA chain termination ▪ Acyclovir-GTP has 100-fold higher affinity for viral DNA than host  DNA Polymerase Inhibitors Indications DNA viruses e.g herpes simplex virus, varicella zoster virus, cytomegalovirus (CMV) retinitis Drug examples Purine analogues: acyclovir, ganciclovir, penciclovir Pyrimidine analogues: idoxuridine, trifluridine Caution Can cross placenta, possibly into breast milk Metabolised in the liver, therefore monitor in hepatic dysfunction Renal elimination, therefore monitor in renal dysfunction  DNA Polymerase Inhibitors ▪ Adverse effects: ▪ Carcinogenic ▪ Mutagenic ▪ Neutropenia ▪ Anaemia ▪ Thrombocytopenia ▪ Nausea & vomiting ▪ Dizziness ▪ Drowsiness & confusion ▪ Nephrotoxicity ▪ Anaphylaxis Neuraminidase Inhibitors  Neuraminidase Inhibitors ▪ Indications: prophylaxis and treatment of influenza A & B ▪ Drugs: 1. Oseltamivir (Tamiflu) – available as an oral preparation; This is an orally active pro-drug activated in gut and liver 2. Zanamavir (Relenza) - available as a powder for inhalation only due to poor oral bioavailability ; drug has restricted usage due to its potential to induce bronchospasms ▪ Increased resistance to these drugs has been seen due to influenza strains differing annually  Biologics: Immunoglobulins ▪ Immunoglobulins are naturally released by activated B cells ▪ Can also be produced via biotechnology ▪ Work against the virus envelope, preventing attachment to host cells ▪ Biologics attach to foreign substances, sending a destruction signal to macrophages and NK cells ▪ Specific immunoglobulins produce immediate protection e.g: ▪ Hepatitis immunoglobulin ▪ Rabies immunoglobulin ▪ Tetanus immunoglobulin ▪ Varicella zoster immunoglobulin  Immunomodulators – Interferons Image adapted from: http://xn--chabnhgan-yj7d6p.vn/interferon-la-gi-nhung-kien-thuc-co-ban-ve-interferon/  Immunomodulators – Interferons ▪ Indications: AIDS-related Kaposi sarcomas, hepatitis B & C, herpes viruses ▪ Inducible, endogenous proteins but can be produced commercially using recombinant DNA technology ▪ MOA: Inhibit translation of viral mRNA into viral proteins ▪ ROA: IV administration with less duration of action after administration ▪ Frequent dosage would be required ▪ Frequency of dosage can be reduced by giving a pegylated version which is a larger molecule and more stable (lengthens duration of action) ▪ Three main types of interferons available: interferon-α, interferon-β and interferon-γ ▪ Side effects: ▪ Alopecia, fever, dizziness, headaches) ▪ Contraindicated in patients with hepatic dysfunction Image adapted from: http://xn--chabnhgan-yj7d6p.vn/interferon-la-gi-nhung-kien-thuc-co-ban-ve-interferon/  HIV ▪ HIV: Human immunodeficiency virus ▪ HIV is a retrovirus, with its genetic material stored on strands of RNA, and complementary DNA (cDNA) is generated from the RNA ▪ End-stage of infection with HIV = acquired immune deficiency syndrome (AIDS) ▪ AIDS is characterized by: ▪ Failure of immune system ▪ Vulnerability to opportunistic infections  HIV Transmission ▪ Blood ▪ Semen and vaginal fluids ▪ Mother-to-child transmission ▪ Accidental needle stick injury ▪ Sharing needles ▪ Artificial insemination with infected sperm sample ▪ Organ transplantation with infected organs ▪ NB!!: HIV is not spread through casual contact, touching an object that an infected individual has handled or kissing* Image adapted from: Wilkins T. HIV 1: epidemiology, pathophysiology and transmission. Nursing Times. 2020;116(7):40-2.  The Goals of ART Achieve and Maintain Virological Suppression Goals of ART With the aim to: Decrease opportunistic infections and other (Antiretroviral HIV-related conditions Minimise the development of treatment treatment) resistance Improve quality of life Reduce new infections by using treatment as prevention Decrease the morbidity and mortality from HIV/AIDS Restoration and/or preservation of immunological function  Antiretroviral Treatment (ART) ▪ Antiretrovirals (ARVs) are ONLY virustatic ▪ Effective against replicating virus ▪ No effect on virus particles in body reservoirs (e.g lymph nodes, eyes) ▪ ART is a Fixed dose combination (FDC) of three synergistic ARVs ▪ It’s clinically unacceptable to start with less than three drugs ▪ A sub-optimal outcome is often experienced with mono- and dual-therapy regimens ▪ Used in an attempt to reduce viral load ▪ Maintains a functional immune system  Classes of ARVs Nucleoside / nucleotide reverse transcriptase inhibitors Non-nucleoside reverse transcriptase inhibitors Protease inhibitors Fusion/entry inhibitors Integrase inhibitors  Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) ▪ Inhibit the enzyme reverse transcriptase (RT) ▪ RT converts single-stranded viral RNA to cDNA which can be inserted into the host’s DNA for replication ▪ NRTIs cause early termination of DNA elongation which leads to no replication of HIV virus Image adapted from: https://step1.medbullets.com/biochemistry/102061/reverse-transcription  NRTIs ▪ Nucleoside analogues (require phosphorylation for them to function) NRTI (used in SA) Analogue mimicked Abacavir Guanosine Didanosine (phased out due to toxicity) Adenosine Emtricitabine Cytidine Lamivudine Cytidine Stavudine (phased out due to toxicity) Thymidine Zidovudine Thymidine ▪ Nucleotide analogues (NtRTIs) (phosphorylated) NRTI (used in SA) Analogue mimicked Tenofovir Adenosine  NRTIs NRTI Comments Abacavir (ABC) Expensive SEs: hypersensitivity reaction (multiple organ), fever, rash, cough, myalgia Emtricitabine (FTC) Comparable to 3TC – biochemically and in resistance profile; Long half-life = once daily dose. SEs: diarrhoea, rash, hyperpigmentation Lamivudine (3TC) Also active in hepatitis B. Hepatitis flares during discontinuation of drug SEs: pancreatitis in paediatric patients Stavudine (d4T) Good CNS penetration. Similar resistance profile with AZT (cross resistance) (phased out) SEs: peripheral neuropathy Zidovudine (AZT) Crosses BBB. Prevents prenatal infection SEs: myalgia, anaemia, bone marrow suppression Tenofovir (TDF) Effective in NRTI-resistant viruses. Bioavailability enhanced by fatty meal SEs: bloating + flatulence, nephrotoxicity, light headedness, hepatomegaly  NRTI dual combinations ▪ Recommended combinations ▪ Tenofovir + lamivudine *Didanosine & ▪ Zidovudine + lamivudine Stavudine phased out in the ARV ▪ Abacavir + lamivudine regimens of South ▪ Tenofovir + emtricitabine Africa due to high rates of AEs ▪ Hazardous combinations ▪ Stavudine + didanosine* ▪ Tenofovir + didanosine ▪ Antagonistic combinations ▪ Stavudine + zidovudine  NRTI Class Side Effects ▪ Various drug-resistant mutations are associated with NRTIs ▪ Common side effects: ▪ Impaired mitochondrial function ▪ Causing hepatic steatosis (increased build-up of fat in liver) + symptomatic hyperlactatemia (lactic acidosis) ▪ Lipodystrophy (fat re-distribution), cardiomyopathy ▪ Myopathy, neuropathy, pancreatitis (inflammation of pancreas) ▪ Myelosuppression (neutropenia + severe anaemia) ▪ NRTIs vary in their ability to do this: ▪ Stavudine > didanosine > zidovudine > lamivudine = abacavir = tenofovir Non Nucleoside Reverse Transcriptase inhibitors (NNRTIs) ▪ Drugs: Efavirenz, Nevirapine, Rilpivirine (RPV), Etravirine (ETV) (used in SA) ▪ Activity limited to HIV-1 only ▪ Bind to reverse transcriptase enzyme, altering its structure = limited mobility and consequently reduced efficiency ▪ Common side effects: Rash, fatigue, headache, GI disturbances, liver dysfunction  (NNRTIs) Nevirapine (NVP) Efavirenz (EFV) Induces CYP3A4 which reduces Preferred NNRTI activity of co-administered ARVs Potent inducer of CYP450 enzymes Lipophilic – found in breast milk and Bioavailability enhanced by fatty meals – possible crosses placenta toxicity therefore best taken on empty stomach Evidence of teratogenicity Side effects in addition to common ones: insomnia, dizziness, depression, nightmares, memory loss, psychosis, impaired concentration  (NNRTIs) Drugs Rilpivirine (RPV) Etravirine (ETV) Comments RPV and ETV are usually reserved for third-line treatment RPV can only be used if the viral load is ˂ 100 000 copies/mL RPV cannot be used with rifampicin Cross resistance is very common within the class of NNRTIs  Protease Inhibitors (PIs) ▪ Drugs: Lopinavir/ Ritonavir (FDC), Atazanavir, Indinavir, Saquinavir, Nelfinavir ▪ Viral protease cleaves proteins into essential enzymes and structural proteins which assemble into a mature virion, therefore PIs target the assembly stage, preventing viral maturation and no new virions can be released ▪ Common side effects: paraesthesia, hyperglycaemia, hypercholesterolemia, lipodystrophy, fatigue, sleep disturbances, rhabdomyolysis, liver dysfunction Protease inhibitors  Protease inhibitors (PIs) ▪ Lopinavir/ ritonavir ▪ First-line PIs ▪ Double the dose or give additional ritonavir when taken concurrently with rifampicin ▪ Saquinavir can also be taken with rifampicin but avoid rifampicin with all other PIs ▪ Disadvantages: ▪ Poorly tolerated ▪ Cross tolerance ▪ Drug interactions common ▪ Pis have poor oral bioavailability – best to take with high-fat meals Never give saquinavir without ▪ Pis are metabolised in the liver by CYP450 enzymes boosting with low dose of ritonavir ▪ Common side effects: Paresthesias, hyperglycaemia, dyslipidaemia, lipodystrophy, sleep disturbances, liver dysfunction ▪ Atazanavir is associated with jaundice and benign hyperbilirubinemia  Fusion Inhibitors - Enfuvirtide ▪ To gain entry, viral transmembrane glycoprotein gp41 undergoes conformation when HIV binds to host cell surface ▪ Enfuvirtide binds to gp41, preventing the conformational change ▪ Enfuvirtide forms part of rescue regimens in cases of: ▪ Multi-drug resistant HIV ▪ Intolerance to other ARVs ▪ Dosage: subcutaneous injection of peptide, twice daily (upper arm/ abdomen/ anterior thigh) ▪ Common side effects: ▪ Flu-like symptoms, headache, dizziness, alterations in mood, gastrointestinal effects, hypersensitivity  Fusion Inhibitors – Maraviroc (MVC) ▪ CCR5 & CXCR4 are host cell surface chemokine receptors and these are hijacked by some strains of HIV to gain entry into cell ▪ HIV may express preference for either CCR5 or CXCR4 or both (dual tropic) ▪ MVC blocks CCR5 receptor = no viral entry ▪ Prior to MVC use: perform test to determine whether strain of HIV uses CCR5, CXCR4 or both ▪ ONLY strains of HIV that use CCR5 to gain access to the cell can be successfully treated with MVC ▪ Caution: Reduce dose when giving with PIs Image adapted from: Medscape®. Mori J, et al. IHIVDRW, 2007. Abstract 10. www.Medscape.com  Integrase Inhibitors (InSTI) Drugs: Raltegravir, Dolutegravir, Elvitagravir ▪ Block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell which subsequently blocks HIV replication ▪ Dolutegravir has fewer side effects and also has less negative interactions with other medicines ▪ SA rolling out new regimen known as TLD: three-in-one, fixed-dose combination that includes dolutegravir, lamivudine, and tenofovir due to increased resistance to NNRTIs DDIs: ▪ Rifampicin lowers levels of dolutegravir; dolutegravir increases levels of metformin; Carbamazepine, phenobarbital & phenytoin (anticonvulsants) + antacids, sucralfate, multivitamin and nutritional supplements decrease concentrations of dolutegravir Side effects: ▪ Insomnia, fatigue, abnormal dreams, anaemia, renal impairment, lipoatrophy (loss of fat tissue)  Drug Regimens 1. First line treatment used in SA = 2NRTIs + DTG e.g., dolutegravir, lamivudine & tenofovir (TLD) ▪ Protease inhibitors are not used first-line as they have long-term toxicity 2. Prevention of mother-to-child transmission: ▪ Newly diagnosed during pregnancy - start FDC immediately 2. Infant regimen (new-born): ▪ Nevirapine at birth and then daily for 6 weeks  Drug Regimens (South Africa) First Line Treatment in Adults and Adolescence Adults and Tenofovir (TDF), Lamivudine (3TC) & dolutegravir Patients must weigh 35 kg or more adolescence (DTG) and be 10 years of age and older For adolescent girls who weigh less than 35 kg, replace TDF with abacavir (ABC) *If contraindications to NRTIs occur, the order of preference for replacement is as follows: Tenofovir (standard adult regimen) Zidovudine, Abacavir First Line Treatment in Infants and Children Neonates (birth to 4 weeks of age) Zidovudine (AZT) + Lamivudine Patients weigh between 2.5 and 3 (3TC) + Nevirapine (NPV) kg Infants & children (≥ 4 weeks of Abacavir (ABC) + 3TC + DTG Patients weigh between 3 and 20 age and ≥ 42 weeks gestational age kg Children (˂ 10 years of age) ABC + 3TC + DTG Patients weigh between 20 & 35 kg  Resistance ▪ Process of reverse transcription is error prone: ▪ Mistakes during transcription lead to mutations causing resistance ▪ Mutations are carried over meaning resistance may occur in treatment naïve patients ▪ Single amino acid substitution may result in patients developing resistance to lamivudine and NNRTIs ▪ Resistance to NRTIs develops slowly (except for lamivudine with high resistance) ▪ Cross resistance is high between NNRTIs ▪ Low chances of resistance with dolutegravir  Fixed Dose ARV Combinations (FDC) Advantages: Increased compliance, cheaper, less side effects, ↑efficacy ▪ Schedule 4 medication ▪ Brand names: ▪ Atripla (Generics: Atroiza, Odimune, Tribuss) ▪ Tenofovir: 300 mg NRTIs ▪ Lamivudine: 300 mg ▪ Dolutegravir: 50 mg InSTI  Post exposure prophylaxis (PEP) ▪ Short-term ARV treatment to reduce the risk of HIV infection after potential exposure ▪ Best results if started 1-2 hours after exposure ▪ Must be within 72 hours of exposure to be effective ▪ Continue treatment for 28 days ▪ Monitor side effects and complications ▪ Medications can have serious side effects that make it difficult to complete the course ▪ NOT 100% effective ▪ Recommended regimen for adults and adolescents: ▪ Tenofovir and emtricitabine or lamivudine plus dolutegravir/raltegravir ▪ Replace raltegravir with atazanavir/ritonavir in pregnancy ▪ Recommended regimen for children (< 35 kg): ▪ Zidovudine and lamivudine plus raltegravir Additional reading for interest's sake Timeline: Moments in the history of HIV ▪ https://www.spotlightnsp.co.za/2019/12/01/timeline-moments-in-the-history-of-hiv/