ANTI-RETROVIRAL

Pharmacology
Nani Maharani
2020
 Human Immunodeficiency Virus
• An RNA retrovirus –
subfamily Lentivirus
• Contains:
• 2 copies of RNA
• Enzymes:
• Reverse Transcriptase
• Integrase
• Protease
• Two major envelope
proteins:
• gp120
• gp41
HIV Life Cycle
Life Cycle of HIV virus
1. Interaction between viral envelope proteins and CD4
receptor and co-receptors leads to binding of the viral
envelope and host cytoplasmic membrane
2. Viral reverse transcriptase catalyses the conversion of viral
RNA into DNA
3. Proviral DNA enters the nucleus and becomes integrated
into chromosomal DNA of host cell (catalyzed by integrase)
4. Expression of viral genes leads to production of viral RNA
and proteins.
5. Protease enzyme cleaves proteins into functional mature
products.
6. Viral proteins and viral RNA are assembled at the cell
surface into the new viral particles and leave the host
through budding.
Antiretrovirals
• Nucleoside/Nucleotide Analogue Reverse Transcriptase Inhibitors
(NRTI’s)
• Block reverse transcriptase activity by incorporating themselves into the
viral DNA and acting as chain terminators in the synthesis of proviral DNA.
• Non-nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTI’s)
• Bind directly and non-competitively with reverse transcriptase, blocking its
activity
• Protease Inhibitors
• Inhibit HIV-1 protease, resulting in release of structurally disorganized and
non-infectious viral particles.
• Fusion Inhibitors
• Inhibit fusion of initial virus with CD4 cell
• Enfuvirtide, Maraviroc
• Only used in salvage therapy
• Integrase Inhibitors
Nucleoside/Nucleotide Reverse
Transcriptase Inhibitors (NRTI’s)
• Include:
• Abacavir (ABC)
• Didanosine (ddI)
• Emtricitabine (FTC)
• Lamivudine (3TC)
• Stavudine (d4T)
• Tenofovir (TDF)
• Zalcitabine (ddC)
• Zidovudine (AZT, ZDV)
• Side Effects:
• Lactic Acidosis
• Hepatic Steatosis
• Peripheral neuropathy
• ***Hypersensitivity reaction with Abacavir  screen for HLA-B*5701
Nucleoside/Nucleotide Reverse
Transcriptase Inhibitors (NRTI’s)
• Zidofudine & Stavudine  dyslipidemia & insulin resistance
• Didanosine toxicity  dose-dependent pancreatitis
• Emtricitabine, Lamivudine: activity against HBV. Sudden
discontinuation may cause hepatitis flare
• Lamivudine: recommended ARV in pregnant women
• Stavudine  dose-related peripheral sensory neuropathy
(reversible), pancreatitis, athralgia, etc.
• Tenofovir  renal failure
• Zidofudine: first-line agent for pregnant women
• Zidofudine  myelosupression (anemia, neutropenia),
gastrointestinal problems, lipoathrophy
Non-nucleoside reverse transcriptase
inhibitors (NNRTI’s)
• Include:
• Nevirapine (NVP)
• Side effects:
• Rash (can cause Stevens Johnson)
• Hepatotoxicity in women with CD4 >/= 250 cells/mm3
• Efavirenz (EFV)
• Side Effects:
• CNS side effects: dizziness, insomnia, hallucinations
• Psychiatric symptoms
• Can cause fetal malformations, neural tube defects
• Delavirdine (DLV)
• Side Effects
• Rash
• Increased transaminases
 Protease Inhibitors
• Include:
• Amprenavir (APV)
• Atazanavir (ATV)
• Fosamprenavir (f-APV)
• Indinavir
• Lopinavir + Ritonavir (Kaletra)
• Nelfinavir
• Ritonavir
• VERY IMPORTANT – Is able to boost levels of other protease inhibitors!
• Saquinavir
• Side Effects
• Cardiac conduction abnormality
• Inhibit CYP450 system
• Hyperlipidemia
• Hyperglycemia
• GI upset
• Kidney stones -- Indinavir
Protease Inhibitors
• Atazanavir: requires acidic medium for absorption,
should not be given in patients with hepatic
insufficiency
• Fosamprenavir: prodrug of amprenavir. Be careful in
hepatic insufficiency
• Indinavir: requires acidic environment to be absorbed,
causes indirect hyperbilirubinemia & nephrolithiasis
• Ritonavir: many potential drug interactions,
combination with Saquinavir is contraindicated  QT &
PR interval prolongation
• Saquinavir: absorption is increased with the present of
fatty foods, many potential drug interactions
Fusion/Entry Inhibitors
• Enfuvirtide: binds to the gp41 subunit  prevent
conformational changes to enter the cell,
Parenterally administered. Side effects: painful
erythematous nodule, headache, nausea,
eosinophillia.
• Maraviroc: binds to CCR5 necessary for entrance of
HIV, hepatic impairement!. Side effects: upper resp
tract infections, allergic reaction.
Integrase Inhibitors
• Dolutegravir: avoid concomitant use with laxatives,
antacids, iron supplements. SE insomnia,
headache, hypersensitivity, liver injury.
• Elvitegravir: in combination with emtricitabine,
tenofovir, cobicistat.
 Antiretrovirals –
When to Start Therapy

Symptomatic HIV Disease Antiretroviral therapy

recommended
Asymptomatic HIV Disease
CD4 count ≤ 200 Antiretroviral therapy
recommended
CD4 count > 200 but <350 Antiretroviral therapy should be
considered and individual decision
(if viral load > 100,000)
CD4 count ≥ 350 Antiretroviral therapy generally not
recommended
Choosing Antiretroviral Regiment
• Need Protease Inhibitor or NNRTI
+
2 – NRTI’s
• Most popular initial regimens:
• Efavirenz + (lamivudine or emtricitabine) + (zidovudine or tenofovir)
• Lopinavir/Ritonavir + (lamivudine or emtricitabine) + zidovudine

• Tenofovir, Emtricitabine and Lamivudine also treat Hepatitis B!

HIV Prophylaxis
• When CD4 count < 200:
• Pneumocystis (PJP) prophylaxis
• Trimethroprim/Sulfamethoxazole (Bactrim) – one DS tab po QDay
If allergy, or unable to tolerate:
• Dapsone (need to check G6PD first!)
• Pentamadine (aerosolized)
• Atovaquone
• When CD4 count < 100
• Toxoplasma gondi prophylaxis:
• Trimethoprim/Sulfamethoxazole – one DS tab po QDay
• Dapsone (Qday) + pyramethamine (Q week) + leucovorin (Q week)
• When CD4 count < 50
• Mycobacterium avium intracellulare prophylaxis
• Azithromycin – 1200 mg po Qweek
Or
• Clarithromycin – 500 mg po q12h
• Please read Basic & Clinical Pharmacology (13th
edition or newer) by Bertram Katzung  Antiviral –
Antiretroviral
Thank you